Gaya, A.M.; (2009) Combination therapy studies with the vascular disruptive agent combretastatin-a4-phosphate (CA4P). Doctoral thesis , UCL (University College London).

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Abstract

CA4P leads to rapid vascular shutdown of tumour core, with minimal effects at the well perfused periphery. CA4P showed minimal anti-tumour activity in single agent phase I studies. This thesis examined the feasibility of CA4P combination therapy, examining the hypothesis that two agents may be additive or synergistic, eliminating separate tumour cell subpopulations and thus increasing the effectiveness of both drugs. Chemotherapy using paclitaxel & carboplatin (UKCTC-207) or 131Iodine anti- CEA radioimmunotherapy (A5B7) was studied. CA4P toxicity was mild and similar to single agent studies - fatigue, tumour pain, flushing, pruritis, headache and hypertension. The DLT was ataxia. A5B7 combination therapy led to dose limiting myelosuppression with minimal efficacy at a 131I-A5B7 dose 66% of single agent antibody MTD. In UKCTC-207, 70% of patients either responded or had disease stability with symptomatic improvement. We also investigated whether CA4P effect is mediated via decreases in cardiac output (CO) and also evaluated heterogeneity of blood flow related dynamic contrast enhanced MRI (DCE-MRI) parameters between different patients and in lesions within patients on the A5B7 study. Increases in CO (mean +14%, p=0.026) occurred after CA4P whilst falls in tumour Ktrans values were seen (mean -25.1%; p=0.011). There was no evidence for CO fall as a cause for reduced Ktrans. Metastatic lesions within-patients were more similar compared to between-patients in DCE-MRI kinetic parameters, both at baseline and in their response to CA4P. A separate perfusion CT analysis revealed no late alterations (over weeks) in tumour blood flow parameters. Correlating DCE-MRI kinetic variable changes following CA4P with tumour immunohistochemical angiogenic markers using standard immunohistochemical techniques, we studied whether the angiogenic profile can explain differential sensitivity of human tumours to CA4P. We found no strong relationships between DCE-MRI variable change following CA4P and the angiogenic markers.

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